Tracking a Tumor's Stealthy Spread

Metastatic cells are a tumor's stealth invaders, infiltrating new sites in the body and growing until they kill. Now, scientists have pinpointed a genetic change that may help colon cancer cells spread to the liver--information that could help researchers develop drugs to stanch the invasion. The work is published online today in Science.

To examine the molecular changes underlying colon cancer metastasis, Kenneth Kinzler, Bert Vogelstein, and their colleagues at the Johns Hopkins Medical Institutions in Baltimore, Maryland, used a technique they developed 6 years ago (Science, 20 October 1995, p. 484). That system, called SAGE (for serial analysis of gene expression), enabled them to compare levels of gene expression in colon cancer cells that had metastasized to the liver with those that hadn't, as well as with normal colon cells.

After painstakingly separating cancer cells from others in the tumors, the scientists identified 144 genes expressed at higher levels in the metastatic tumor cells and 79 expressed at lower levels. They decided to focus on one poorly understood enzyme, PRL-3, a tyrosine phosphatase thought to foster cell growth. They found that normal colon epithelia cells showed little or no expression of the gene, but that its expression increased somewhat in primary colon tumors that hadn't metastasized, and significantly more in all the liver metastases examined. This indicates that an excess of the enzyme helps the cancer spread. The clincher came when the team found extra copies of the PRL-3 gene in three of 12 metastases. Such copies are unstable and tend to be lost, Vogelstein says, unless they provide a selective advantage.

What that advantage might be, and how it might contribute to colon cancer metastasis is not yet known. But other researchers are already enthusiastic. While many gene changes have been tied to the early stages of cancer development, this is one of only a few that have been linked to metastasis, notes Jeffrey Trent of the National Human Genome Research Institute in Bethesda, Maryland.